Tramadol (cis-2-dimethylaminomethyl-1-(3-methoxy-phenyl)-1-cyclohexanol) is a chiral drug substance which is used as a high-potency analgesic agent. Although tramadol is currently marketed as the racemate only, there has been considerable interest in the physiological properties associated with its individual enantiomers, namely 1S, 2S-(-)-tramadol and 1R, 2R-(+)-tramadol, the latter shown below as (1). For example, lead references to literature on this topic are highlighted in WO-A-9840053. It is possible that further investigations in this field will lead to a better understanding of the pharmacology of tramadol enantiomers, which could in turn allow for improved pharmaceutical compositions to be identified. ##STR1##
In connection with our own interest in this area, we required an efficient and reliable method for the preparation of individual enantiomers of tramadol. Due to the ready availability of racemic tramadol a classical resolution process, involving separation of diastereomeric salts by selective crystallisation, appeared ideal for this purpose.
Initially, literature procedures for the resolution of tramadol were investigated. In U.S. Pat. No. 5,723,668, it is reported that use of L-(+)-tartaric acid as resolving agent facilitates a highly efficient resolution whereby 49% yield (with respect to racemic base) of a diastereomerically-pure salt of 1S, 2S-(-)-tramadol is obtained after a single crystallisation from ethanol solution, by filtration and washing with solvent. However, in our hands, these results could not be reproduced. Typically, following dissolution of racemic tramadol and L-(+)-tartaric acid, we observed crystallisation, but analysis of the isolated salt showed little or no diastereomeric enrichment.
Another resolution process is described in U.S. Pat. No. 3,830,934, in which O,O-dibenzoyl-D-tartaric acid is used as resolving agent. Our own investigation of this process indicated that at least three cycles of dissolution-crystallisation-filtration are required in order to obtain salt of &gt;98% de (diastereomeric excess), corresponding to &gt;98% ee (enantiomeric excess) tramadol free base after cracking. Thus the process may be suitable as a small-scale preparative method. However, the need for multiple crystallisation cycles with cumulative lowering of yields may render the process unsuitable and economic for operation on a larger scale, e.g. for manufacturing processes.